LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory

Abstract

Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that forms a trans-synaptic complex that includes the presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23), which interacts with voltage-gated potassium channels K v 1.1, and the postsynaptic ADAM22, which interacts with AMPA receptors. Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures. Although there is evidence that this disease is immune-mediated, the underlying LGI1 antibody-mediated mechanisms are unknown. Here, we used patient-derived immunoglobulin G (IgG) antibodies to determine the main epitope regions of LGI1 and whether the antibodies disrupt the interaction of LGI1 with ADAM23 and ADAM22. In addition, we assessed the effects of patient-derived antibodies on K v 1.1, AMPA receptors, and memory in a mouse model based on cerebroventricular transfer of patient-derived IgG. We found that IgG from all patients (n = 25), but not from healthy participants (n = 20), prevented the binding of LGI1 to ADAM23 and ADAM22. Using full-length LGI1, LGI3, and LGI1 constructs containing the LRR1 domain (EPTP1-deleted) or EPTP1 domain (LRR3-EPTP1), IgG from all patients reacted with epitope regions contained in the LRR1 and EPTP1 domains. Confocal analysis of hippocampal slices of mice infused with pooled IgG from eight patients, but not pooled IgG from controls, showed a decrease of total and synaptic levels of K v 1.1 and AMPA receptors. The effects on K v 1.1 preceded those involving the AMPA receptors. In acute slice preparations of hippocampus, patchclamp analysis from dentate gyrus granule cells and CA1 pyramidal neurons showed neuronal hyperexcitability with increased glutamatergic transmission, higher presynaptic release probability, and reduced synaptic failure rate upon minimal stimulation, all likely caused by the decreased expression of K v 1.1. Analysis of synaptic plasticity by recording field potentials in the CA1 region of the hippocampus showed a severe impairment of long-term potentiation. This defect in synaptic plasticity was independent from K v 1 blockade and was possibly mediated by ineffective recruitment of postsynaptic AMPA receptors. In parallel with these findings, mice infused with patient-derived IgG showed severe memory deficits in the novel object recognition test that progressively improved after stopping the infusion of patient-derived IgG. Different from genetic models of LGI1 deficiency, we did not observe aberrant dendritic sprouting or defective synaptic pruning as potential cause of the symptoms. Overall, these findings demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1 signalling, causing neuronal hyperexcitability, decreased plasticity, and reversible memory deficits.

Persistent sodium current blockers can suppress seizures caused by loss of low‐threshold D‐type potassium currents: Predictions from an in silico study of Kv1 channel disorders

“…Our simulations suggest that enhanced excitatory transmission is likely to be the consequence of a higher level of neurotransmitter release caused by widened APs. Though the loss of the leucine‐rich glioma‐inactivated 1 protein is associated with reduced expression of AMPA receptor GluA1 subunits, resulting in smaller postsynaptic currents, this effect is outweighed by increases in postsynaptic currents via NMDA receptors. Because inactivation of NMDA receptors is much slower than that of AMPA receptors, the net effect of LGI1 loss‐of‐function mutations is likely to be to lengthen PSCs.…”

“…Associated epilepsy phenotypes can be refractory to existing antiepileptic medications, often with devastating sequelae. LGI1 encodes a protein that regulates the expression and function of K v 1 channels and AMPA receptors . In LGI1 knockout models, the expression of K v 1.1 and K v 1.2 channels is reduced by more than 50% .…”

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

“…Previous studies revealed that most sera from LGI1 encephalitis patients compete with the ligand–receptor interaction between LGI1 and ADAM22 in contrast to sera from patients with the peripheral nerve disorder neuromyotonia containing autoantibodies to LGI1 . Furthermore, a serum competing with ADAM22 binding to LGI1 induced a reversible reduction in synaptic AMPAR clusters in neuronal cultures .…”

“…Antibody‐mediated interference with the LGI1–ADAM22–PSD‐95 link is expected to alter the composition of the postsynaptic density as well. This might result in deficient AMPAR recruitment and underlie cognitive deficits in LGI1 encephalitis. It is possible that the inhibitory effects of LGI1 antibodies are limited by the accessibility of mature synaptic structures and are detected only after long exposition times.…”

“…22 Furthermore, continuous intraventricular infusion of such IgG preparations into the CSF of mice enhanced glutamatergic neurotransmission by increasing presynaptic excitability in 2 pathways. 23 Injection of human CSF containing LGI1 antibodies into the dorsal hippocampus of mice increased both the probability of glutamate release from CA3 neurons and the amplitude of population spikes in the CA1 area following Schaffer collateral stimulation. 24 Although immunosuppression is effective in 50 to 80% of patients with LGI1 encephalitis, 4 detailed insight into the composition of the humoral autoimmune response to LGI1 in the CSF and the role of single LGI1 antibodies is missing.…”